The present invention relates to novel stabilizers of radiopharmaceutical compositions used for diagnosis and therapy. In particular, the invention relates to use of a hydrophilic 6-hydroxy-chroman derivative to increase the shelf-life of diagnostic and therapeutic radiopharmaceuticals.
A number of radionuclides are routinely employed in nuclear medicine, both as diagnostic agents and as therapeutics. For example, 99mTc, 111In, 18F, and 201Tl are employed as diagnostic imaging agents, and 131I, 32P, 89Sr, and 153Sm are in therapeutic use. In addition, nuclides such as 186Re, 188Re, 212Bi, 213Bi, 90Y, 67Cu, 192Ir, 165Dy, and 117mSn have been proposed as potential therapeutic agents. Such radionuclides are administered in the form of radiopharmaceutical compositions, which generally include a chelator for the nuclide. Radiopharmaceuticals may additionally include a targeting molecule such as a monoclonal antibody, an antibody fragment, or a receptor ligand. The availability of radiopharmaceuticals has significantly advanced diagnosis and treatment of a variety of diseases.
Chemical decomposition may limit a radiopharmaceutical's shelf life by decreasing the radiochemical purity of the agent over time. For example, a radiopharmaceutical containing 99mTc, 186Re, or 188Re may be susceptible to oxidation of the nuclide itself. In addition, the radiation emitted from a radionuclide can break chemical bonds of other components of the composition, thus causing autoradiolysis. Autoradiolysis is a particular problem when the radiopharmaceutical contains higher energy nuclides, such as β-emitters (e.g., 186Re, 188Re, 90Y, 131I) and α-emitters (e.g., 213Bi, 212Bi, 211At, 225Ac, 223Ra).
Thus many radiopharmaceuticals require stabilizers to maximize shelf life. Such stabilizers must be non-toxic and must be able to maintain the product's radiochemical purity for an acceptable shelf-life as well as during use. In addition, an acceptable radiopharmaceutical stabilizer must not interfere with delivery of the radionuclide to the target site.
Methods for stabilizing radiopharmaceuticals by adding gentisates are disclosed, for example, in U.S. Pat. Nos. 4,232,000; 4,233,284; 4,497,744; 5,384,113. Stabilization of radiopharmaceuticals using ascorbic acid is disclosed in U.S. Pat. Nos. 5,393,512 and 5,011,676, in WO 97/28181 and in WO 98/33531. Hydroquinone stabilizers of radiopharmaceuticals is disclosed in U.S. Pat. No. 4,229,427. Other compounds such as reductic acid, erythorbic acid, p-aminobenzoic acid, 4-hydroxybenzoic acid, nicotinic acid, nicotinamide, 2,5-dihydroxy-1,4-benzenedisulfonic acid, tartaric acid, inositol, and the like, have also been used to stabilize radiopharmaceutical compositions.
U.S. Pat. No. 5,384,113 discloses a method of preventing autoradiolysis of peptides radiolabelled with 111In using gentisic acid or gentisyl alcohol. In addition to preventing autoradiolysis of peptides by 111In, the method of U.S. Pat. No. 5,384,113 is proposed to prevent autoradiolysis of peptides by 67Ga, 169Yb, 125I, 123I, and 201Tl. Two radiolabelled peptides, 111In-DTPA-octreotide and 123I-LHRH, were tested for autoradiolysis prevention. A monoclonal antibody, NR-Lu-10, labelled with 186Re was also specifically exemplified.
As indicated in Example 1, infra, the present inventors have found that that when added as a component in radiopharmaceutical kit formulations, gentisic acid decreases the radiochemical purity of some 99mTc-labelled peptides, and thus is not useful as a stabilizer of some radiolabelled peptides. A need exists, therefore, for additional stabilizers of radiopharmaceuticals. A particular need exists for stabilizers of radiopharmaceuticals containing less than 70 amino acids linked by peptide bonds.
U.S. Pat. Nos. 3,947,473, 4,003,919, 4,018,799 and 4,026,907 disclose a variety of antioxidant hydrophilic 6-hydroxy-chroman compounds as intermediates in preparation of optically active α-tocopherol. U.S. Pat. No. 4,511,685 discloses hydrophilic 6-hydroxy-chroman derivatives and use of such derivatives to stabilize polypropylene compositions. U.S. Pat. Nos. 4,847,267 and 4,970,216 disclose use of one such hydrophilic 6-hydroxy-chroman, 6-hydroxy-2,5,7,8-tetramethyl-2-carboxylic acid alone or in combination with sulfur compounds, including glutathione or cysteine, as a skin treatment composition to inhibit generation of free radicals in the skin.